Chronic Toxoplasma gondii Infection Induces Anti- N -Methyl-d-Aspartate Receptor Autoantibodies and Associated Behavioral Changes and Neuropathology

Anti-NMDA receptor (NMDAR) autoantibodies have been postulated to play a role in the pathogenesis of NMDAR hypofunction, which contributes to the etiology of psychotic symptoms. is a pathogen implicated in psychiatric disorders and associated with elevation of NMDAR autoantibodies. However, it remai...

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Bibliographic Details
Published in:Infection and immunity 2018-10, Vol.86 (10)
Main Authors: Li, Ye, Viscidi, Raphael P, Kannan, Geetha, McFarland, Ross, Pletnikov, Mikhail V, Severance, Emily G, Yolken, Robert H, Xiao, Jianchun
Format: Article
Language:English
Subjects:
Animals
Autoantibodies - immunology
Behavior, Animal
Brain - immunology
Brain - parasitology
Brain - pathology
Brain - physiopathology
Chronic Disease
Disease Models, Animal
Female
Fungal and Parasitic Infections
Humans
Male
Mice
Mice, Inbred BALB C
Motor Activity
Neuropathology
Receptors, N-Methyl-D-Aspartate - immunology
Toxoplasma - physiology
Toxoplasmosis - immunology
Toxoplasmosis - parasitology
Toxoplasmosis - pathology
Toxoplasmosis - psychology
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Summary:Anti-NMDA receptor (NMDAR) autoantibodies have been postulated to play a role in the pathogenesis of NMDAR hypofunction, which contributes to the etiology of psychotic symptoms. is a pathogen implicated in psychiatric disorders and associated with elevation of NMDAR autoantibodies. However, it remains unclear whether parasite infection is the cause of NMDAR autoantibodies. By using mouse models, we found that NMDAR autoantibody generation had a strong temporal association with tissue cyst formation, as determined by MAG1 antibody seroreactivity ( = 0.96; < 0.0001), which is a serologic marker for the cyst burden. The presence of MAG1 antibody response, but not IgG response, was required for NMDAR autoantibody production. The pathogenic relevance of NMDAR autoantibodies to behavioral abnormalities (blunted response to amphetamine-triggered activity and decreased locomotor activity and exploration) and reduced expression of synaptic proteins (the GLUN2B subtype of NMDAR and PSD-95) has been demonstrated in infected mice. Our study suggests that NMDAR autoantibodies are specifically induced by persistent infection and are most likely triggered by tissue cysts. NMDAR autoantibody seroreactivity may be a novel pathological hallmark of chronic toxoplasmosis, which raises questions about NMDAR hypofunction and neurodegeneration in the infected brain.
ISSN:0019-9567
1098-5522
DOI:10.1128/iai.00398-18